Abstract 276: Enhancing standard chemotherapy response by targeted inhibition of MAPK signaling pathways in experimental pancreatic cancer

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis of all solid tumors, with an overall survival rate of less than 6%. Gemcitabine (Gem) remained the standard of care agent over the past 16 years despite limited clinical benefits. Nab-paclitaxel (NPT), a water-soluble albumin-bound formulation of paclitaxel, has recently shown greater efficacy in advanced PDAC. Nab-paclitaxel combination with gemcitabine is now standard of care for advanced PDAC. More than 90% of PDAC tumors harbor an activating mutation in the KRAS oncogene. Since to date no therapeutics have effectively targeted this oncogene product, alternative strategies focus on inhibition of downstream effectors of KRAS signaling pathways. Trametinib (Tra) is a small molecule inhibitor of the RAF-MEK-ERK (MAPK) signaling pathway that is a well-described mediator of KRAS induced transformation and tumorigenesis. In the present preclinical study, we evaluated combination treatment benefits of the standard chemotherapeutics with trametinib to define a novel therapeutic strategy for PDAC. Median animal survival over controls (20 days) in human intraperitoneal PDAC xenografts was significantly improved by NPT (33 days, a 65% increase, p = 0.0004), Gem (26 days, a 30% increase, p = 0.002), NPT+Gem (39 days, a 95% increase, p = 0.0001) and Tra (31 days, a 55% increase, p = 0.0004) therapy. Survival was further increased by addition of trametinib to chemotherapy: NPT+Tra (median: 37 days, a 85% increase, p = 0.0001), Gem+Tra (34 days, a 70% increase, p = 0.0001) and NPT+Gem+Tra (49 days, a 145% increase, p<0.0001). Treatment of subcutaneous tumor-bearing mice with chemotherapy and trametinib resulted in significant tumor growth inhibition. Net tumor growth in different therapy groups over two weeks varied between controls (432.6 mm3), NPT (105.3 mm3), Tra (184 mm3), NPT+Tra (81 mm3), NPT+Gem (37.3 mm3), and NPT+Gem+Tra (-8.1 mm3). Mean tumor weight (in g) in different therapy groups was as follows: controls 0.38±0.06, NPT 0.23±0.06, Tra 0.31±0.03, NPT+Tra 0.23±0.06, NPT+Gem 0.15±0.05 and NPT+Gem+Tra 0.11±0.05. In vitro studies demonstrated inhibition in PDAC cell (AsPC-1, Panc-1, Mia PaCa-2, CFPAC) proliferation by treatment with NPT+Gem, trametinib, and combination. Immunoblot analysis revealed that trametinib effects were accompanied by decrease in phospho-ERK expression and increase in the expression of apoptosis-related cleaved caspase-3 protein. These findings suggest that the effects of the standard chemotherapeutic regimens can be enhanced through specific inhibition of downstream components of the MAPK signaling pathway, which clinically could lead to improved PDAC therapy effects. Citation Format: Niranjan Awasthi, Sheena Monahan, Margaret A. Schwarz, Roderich E. Schwarz. Enhancing standard chemotherapy response by targeted inhibition of MAPK signaling pathways in experimental pancreatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 276.